Patent FR-2866885-A1 (FR)
Title: New 1-alkyl-piperidine-4-carbamate derivatives and analogs, are fatty acid amidohydrolase inhibitors useful e.g. for treating pain, cancer or neurodegenerative, cardiovascular, inflammatory or allergic disease
Inventor: ABOUABDELLAH AHMED
IPC: C07D207/09
Filed: 2004-02-26
Abstract: Carbamoylalkyl 1-((hetero)aryl-substituted alkyl)-azetidine, pyrrolidine, piperidine or homopiperidine-carbamates (I) are new. Azetidine, pyrrolidine, piperidine or homopiperidine derivatives of formula (I) and their acid addition salts, hydrates and solvates are new. m : 1-4; n : 1-3; o : 1 or 2; A : one or more of X, Y and/or Z; X : CH 2 (optionally substituted (os) by 1 or 2 of alkyl, cycloalkyl or cycloalkyl-(1-3C) alkyl); Y : 2C alkenylene (os by 1 or 2 of alkyl, cycloalkyl or cycloalkyl-(1-3C) alkyl) or 2C alkynylene; Z : 3-7C cycloalkylidene or 3-7C cycloalkylene; B : direct bond or 1-6C alkylene; G : direct bond, O, S, CH(OH), CO, SO or SO 2; R 1R 4 (os by one or more groups R 5 and/or R 6); R 4furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, thiadiazolyl, isothiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, naphthalenyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridinyl, furopyridinyl, dihydrofuropyridinyl, thienopyridinyl, dihydrothienopyridinyl, imidazopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, oxazolopyridinyl, isoxazolopyridinyl or thiazolopyridinyl; R 5halo, CN, NO 2, alkyl, alkoxy, OH, alkylthio, fluoroalkyl, fluoroalkoxy, fluoroalkylthio, NR 7R 8, NR 7COR 8, NR 7COOR 8, NR 7SO 2R 8, COR 7, COOR 7, CONR 7R 8, SO 2R 7, SO 2NR 7R 8 or 1-3C alkylenedioxy; R 6phenyl, phenoxy, benzyloxy, naphthalenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl (all os by one or more groups R 5); R 7, R 8H or alkyl; or NR 7R 8azetidino, pyrrolidino, piperidino, morpholino, thiomorpholino, azepino or piperazino (all os by alkyl or benzyl); R 2H or alkyl; R 3H, alkyl, cycloalkyl or cycloalkyl-(1-3C) alkyl; alkyl moieties have 1-6C and cycloalkylene moieties 3-7C unless specified otherwise. Independent claims are included for: (A) the preparation of (I); and (B) oxazolidinedione and carbamate-amide derivative intermediates of formulae (IIa) and (Ia) as new compounds, provided that 3-(1-(phenylmethyl)-4-piperidinyl)-2,4-oxazolidinedione is excluded as (IIa). [Image] ACTIVITY : Analgesic; antimigraine; auditory; antiemetic; anorectic; immunomodulator; neuroleptic; relaxant; tranquilizer; antidepressant; neuroprotective; antiparkinsonian; nootropic; anticonvulsant; cerebroprotective; nephrotropic; cardiant; hypotensive; antiarrythmic; antiarteriosclerotic; vasotropic; cytostatic; immunosuppressive; antipsoriatic; dermatological; antianemic; antiallergic; antiparasitic; virucide; antibacterial; anti-HIV; antiinflammatory; antiarthritic; antirheumatic; osteopathic; antigout; ophthalmological; antitussive; antiasthmatic; antiulcer; antidiarrheic; uropathic. In phenylbenzoquinone-induced writhing tests for analgesic activity in mice, the most active compounds (I) (not specified) inhibited writhing by 35-70% at doses of 1-30 mg/kg p.o. or i.p. MECHANISM OF ACTION : Fatty acid amidohydrolase (FAAH) inhibitor. 2-(Methylamino)-2-oxoethyl ((1-(2-((2,4-dichlorophenyl)-oxy)-ethyl)-piperidin-4-yl)-methyl)-carbamate hydrochloride (I') had IC 50 49 nM for inhibition of FAAH.